6-1611567-GGGCGGCGGC-GGGC

Variant names:

• chr6-1611567-GGGCGGC-G
• rs76840944
• NM_001453.3:c.1136_1141delGCGGCG

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM1 BS1 BS2

The NM_001453.3(FOXC1):​c.1136_1141delGCGGCG​(p.Gly379_Gly380del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000621 in 1,142,748 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. G379G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000061 (0 hom., cov: 24)
  • Exomes 𝑓: 0.000062 (1 hom.)
• Consequence: FOXC1 NM_001453.3 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.46
• Publications: 6 publications found

Genes affected

FOXC1 (HGNC:3800): (forkhead box C1) This gene belongs to the forkhead family of transcription factors which is characterized by a distinct DNA-binding forkhead domain. The specific function of this gene has not yet been determined; however, it has been shown to play a role in the regulation of embryonic and ocular development. Mutations in this gene cause various glaucoma phenotypes including primary congenital glaucoma, autosomal dominant iridogoniodysgenesis anomaly, and Axenfeld-Rieger anomaly. [provided by RefSeq, Jul 2008]

FOXC1 Gene-Disease associations (from GenCC):

• anterior segment dysgenesis 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• Axenfeld-Rieger syndrome type 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• aniridia

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• Axenfeld anomaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Axenfeld-Rieger syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• isolated aniridia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Peters anomaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Rieger anomaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_001453.3
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000614 (9/146528) while in subpopulation SAS AF = 0.00104 (5/4794). AF 95% confidence interval is 0.00041. There are 0 homozygotes in GnomAd4. There are 6 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High AC in GnomAd4 at 9 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001453.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXC1	NM_001453.3	MANE Select	c.1136_1141delGCGGCG	p.Gly379_Gly380del	disruptive_inframe_deletion	Exon 1 of 1	NP_001444.2	W6CJ52

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXC1	ENST00000645831.2	MANE Select	c.1136_1141delGCGGCG	p.Gly379_Gly380del	disruptive_inframe_deletion	Exon 1 of 1	ENSP00000493906.1	Q12948

Frequencies

GnomAD3 genomes AF: 0.0000615 AC: 9 AN: 146426 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000606

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000622 AC: 62 AN: 996220 Hom.: 1 AF XY: 0.0000672 AC XY: 32 AN XY: 475954

African (AFR) AF: 0.00 AC: 0 AN: 19812

American (AMR) AF: 0.00 AC: 0 AN: 5788

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11264

East Asian (EAS) AF: 0.000360 AC: 4 AN: 11126

South Asian (SAS) AF: 0.000397 AC: 9 AN: 22672

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 15102

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2442

European-Non Finnish (NFE) AF: 0.0000517 AC: 45 AN: 871222

Other (OTH) AF: 0.000109 AC: 4 AN: 36792

GnomAD4 genome AF: 0.0000614 AC: 9 AN: 146528 Hom.: 0 Cov.: 24 AF XY: 0.0000841 AC XY: 6 AN XY: 71316

African (AFR) AF: 0.00 AC: 0 AN: 40870

American (AMR) AF: 0.00 AC: 0 AN: 14764

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3388

East Asian (EAS) AF: 0.00 AC: 0 AN: 4836

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8696

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000607 AC: 4 AN: 65952

Other (OTH) AF: 0.00 AC: 0 AN: 2034

Alfa AF: 0.00 Hom.: 107

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Axenfeld-Rieger syndrome type 3 (2)
-	1	-	Axenfeld-Rieger syndrome type 3;C5975707:Anterior segment dysgenesis 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.5
Mutation Taster		=193/7	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs76840944; hg19: chr6-1611802;